In the first part of the study, skin biopsies will be collected from the leg from
children with a normal neurological development (healthy children) in the setting of
elective orthopedic surgery (during general anesthesia; from surgical crop margins).
The IENFD is determined by staining and quantification of PGP9.5-positive intraepidermal
nerve fibers on 40 µm thick skin sections.
The skin biopsies will be collected from the site of orthopedic surgical procedure. For
example, if the child is undergoing corrective osteotomy of genu valgum, the skin biopsy
is drawn from the most distal part of surgical incision sides (distal leg); if the child
is undergoing orthopedic surgery in the context of epiphyseolysis capitis femoris, the
skin biopsy is drawn from the thigh (proximal leg):
In adults, the IENFD is higher in specimens derived from the proximal leg than in skin
from the distal leg. Because in small fiber neuropathy the small nerve fiber degeneration
often starts distally, the recommended sampling site for the quantification of IENFD in
adults is the distal leg. That is why the calculation of the 5th percentile as the cutoff
for reduced IENFD in children will be based on skin biopsies collected from the distal
leg.
Due to the limited number of surgeries on the distal leg and distal biopsies in certain
age groups of healthy participants (e.g. 4-8), cases with skin biopsies taken from the
proximal leg will also be included. The IENFD from cases drawn from the proximal leg and
cases from the distal leg will be compared. The samples drawn from the distal or proximal
leg will be labelled accordingly. If the IENFD is comparable between the distal and
proximal cases, a pooled analysis including proximal and distal cases will be performed.
In the second part of the study, skin biopsies from the distal leg will be collected from
children with neurodevelopmental disorders of acquired, genetic and initially unexplained
etiology in the setting of local anesthesia, whenever possible during an elective
intervention with sedation/general anesthesia. IENFD below the predicted age- and
sex-specific 5th percentile will be classified "reduced", otherwise as "normal".
A literature review will be performed to identify those neurodevelopmental disorders that
have been associated with peripheral neuropathy in the past.
In cases with a yet unexplained etiology of neurodevelopmental disorder (no perinatal
asphyxia, postnatal asphyxia, no cardiopulmonary resuscitation, no extreme prematurity,
no encephalitis others, no stroke, or cerebral tumor), genetic testing (exome or genome
sequencing and microarray analysis) will be performed.
Clinical symptoms of SFN (distal sensory signs and autonomic dysfunction) In adults the
diagnosis of SNF is also based on the presence of distal sensory signs. Therefore, all
participants or their legal guardians will be requested to answer questionnaires
[(SFN-symptom inventory questionnaire (SFN-SIQ) and the SFN-Screening list (SFNSL)] that
specifically assess distal sensory and autonomic symptoms related to SFN.
Additional exploratory subgroup analysis 1): In adults the diagnosis of SNF is also based
on abnormal thermal perception assessed by quantitative sensory testing (QST). In
collaboration with the University Children´s Hospital of the Ruhr University Bochum, QST
will be performed in those children that are old enough and who have the cognitive
ability to undergo QST. Small nerve fiber function including thermal perception will be
assessed.
Additional exploratory subgroup analysis 2): Small fiber neuropathy can be associated
with large fiber neuropathy. Therefore, the proportion of abnormal findings of
electrophysiological studies in medical record of children with a reduced versus normal
IENFD will be assessed.
